As Karl Rahner's assistant, he worked at the universities of Munich and Münster, but also experienced the Second Vatican Council in Rome at close quarters. At the age of just 32, he was appointed to the chair of Catholic dogmatics and theological propaedeutics in Mainz; three years later, he took over the professorship of dogmatics and ecumenical theology in Freiburg. In 1983, Prof. Dr. Dr. Karl Lehmann was elected and appointed Bishop of Mainz and received his episcopal consecration in Mainz Cathedral. In 1987, he was elected Chairman of the German Bishops' Conference, and in 1993 and 1999 he was re-elected to this office for a further six years. On January 28, 2001, Pope John Paul II appointed Bishop Lehmann as cardinal. On May 16, 2016, Karl Lehmann's 80th birthday, Pope Francis accepted his resignation as Bishop of Mainz.

In addition to his main offices, Karl Lehmann was involved in many other institutions and committees: from 1971 to 1975 in the Joint Synod of the Dioceses in Germany, from 1969 to 1983 in the Central Committee of German Catholics, from 1969 to the present in the Ecumenical Working Group of Protestant and Catholic Theologians, from 1974 to 1984 in the International Theological Commission at the Holy See in Rome, and since 1969 in the Faith Commission of the German Bishops' Conference.

He was also a member of the Congregation for Bishops and for the Eastern Churches, the Pontifical Council for Promoting Christian Unity, the Academy of Sciences and Literature in Mainz, and the European Academy of Sciences in Salzburg. In 1991, he received honorary doctorates from the University of Innsbruck and the Catholic University in Washington, D.C., in 1994 from the Catholic University of Maynooth, Ireland, in 1997 from the Catholic Theological Academy in Warsaw, in 2000 from the Faculty of Theology at the Karl-Franzens-University in Graz, and in 2002 from the University of Opole, Poland. Bishop Lehmann was awarded the Grand Cross of Merit with Star and Sash and the Ring of Honor of the Görres Society. In the 2004/2005 campaign, he was awarded the "Order Against Deadly Seriousness" by the Aachen Carnival Association.

In 2023, the Diocese of Mainz published a report prepared with external expertise that critically examines the role of Cardinal Karl Lehmann in cases of abuse within the Church. The so-called EVV report is published on the diocese's website and can be accessed there via a link to the website of attorney Ulrich Weber.